Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vi...
Gespeichert in:
| Veröffentlicht in: | Chemical biology & drug design 2019-10, Vol.94 (4), p.1813-1823 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1823 |
|---|---|
| container_issue | 4 |
| container_start_page | 1813 |
| container_title | Chemical biology & drug design |
| container_volume | 94 |
| creator | Mishra, Rama K. Clutter, Matthew R. Blyth, Gavin T. Kosciuczuk, Ewa M. Blackburn, Amy Z. Beauchamp, Elspeth M. Schiltz, Gary E. Platanias, Leonidas C. |
| description | Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase. |
| doi_str_mv | 10.1111/cbdd.13585 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6800066</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2250619560</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4205-362bd9e3dec08b1f0ae93c7bb67dad9cb6c17e692f7d5478408f0683ab258ef43</originalsourceid><addsrcrecordid>eNp9kctuEzEUhi0EoqWw4QGQlwgpxfaML7NBgoRLpSI2sLZ8m4zLxA6-BGXHI_CMPAkuaaOyqTc-tj99Pjo_AM8xOsdtvTba2nPcUUEfgFPMe75ARNCHx5rzE_Ak5yuE-p4S8RicdJgwhAU9BVcrn03cubSHcYShVTP8HL5DHyavfYkpw5p9WMNNLar4GP78-q1VdrYRthpn23n0Be58KlXNcPLrqV2VKcW6nra1wGySc6EpnoJHo5qze3azn4FvH95_XX5aXH75eLF8e7kwPUF00TGi7eA66wwSGo9IuaEzXGvGrbKD0cxg7thARm5pz0WPxIiY6JQmVLix787Am4N3W_XGWeNCSWqW2-Q3Ku1lVF7-_xL8JNdxJ5lACDHWBC9vBCn-qC4XuWlDcvOsgos1S0IoYnigDDX01QE1Keac3Hj8BiN5HY68Dkf-C6fBL-42dkRv02gAPgA__ez296jk8t1qdZD-BXXqoJ4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2250619560</pqid></control><display><type>article</type><title>Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Mishra, Rama K. ; Clutter, Matthew R. ; Blyth, Gavin T. ; Kosciuczuk, Ewa M. ; Blackburn, Amy Z. ; Beauchamp, Elspeth M. ; Schiltz, Gary E. ; Platanias, Leonidas C.</creator><creatorcontrib>Mishra, Rama K. ; Clutter, Matthew R. ; Blyth, Gavin T. ; Kosciuczuk, Ewa M. ; Blackburn, Amy Z. ; Beauchamp, Elspeth M. ; Schiltz, Gary E. ; Platanias, Leonidas C.</creatorcontrib><description>Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.</description><identifier>ISSN: 1747-0277</identifier><identifier>EISSN: 1747-0285</identifier><identifier>DOI: 10.1111/cbdd.13585</identifier><identifier>PMID: 31260185</identifier><language>eng</language><publisher>England</publisher><subject>AML ; Drug Discovery ; eIF4E ; Glide ; Humans ; IFD ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - metabolism ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - enzymology ; Mnk1 ; Mnk2 ; Molecular Docking Simulation ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - metabolism ; Protein Kinase Inhibitors - chemistry ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; vHTS</subject><ispartof>Chemical biology & drug design, 2019-10, Vol.94 (4), p.1813-1823</ispartof><rights>2019 John Wiley & Sons A/S</rights><rights>2019 John Wiley & Sons A/S.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4205-362bd9e3dec08b1f0ae93c7bb67dad9cb6c17e692f7d5478408f0683ab258ef43</citedby><cites>FETCH-LOGICAL-c4205-362bd9e3dec08b1f0ae93c7bb67dad9cb6c17e692f7d5478408f0683ab258ef43</cites><orcidid>0000-0003-4180-5051</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcbdd.13585$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcbdd.13585$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,782,786,887,1419,27931,27932,45581,45582</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31260185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mishra, Rama K.</creatorcontrib><creatorcontrib>Clutter, Matthew R.</creatorcontrib><creatorcontrib>Blyth, Gavin T.</creatorcontrib><creatorcontrib>Kosciuczuk, Ewa M.</creatorcontrib><creatorcontrib>Blackburn, Amy Z.</creatorcontrib><creatorcontrib>Beauchamp, Elspeth M.</creatorcontrib><creatorcontrib>Schiltz, Gary E.</creatorcontrib><creatorcontrib>Platanias, Leonidas C.</creatorcontrib><title>Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening</title><title>Chemical biology & drug design</title><addtitle>Chem Biol Drug Des</addtitle><description>Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.</description><subject>AML</subject><subject>Drug Discovery</subject><subject>eIF4E</subject><subject>Glide</subject><subject>Humans</subject><subject>IFD</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Mnk1</subject><subject>Mnk2</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>vHTS</subject><issn>1747-0277</issn><issn>1747-0285</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuEzEUhi0EoqWw4QGQlwgpxfaML7NBgoRLpSI2sLZ8m4zLxA6-BGXHI_CMPAkuaaOyqTc-tj99Pjo_AM8xOsdtvTba2nPcUUEfgFPMe75ARNCHx5rzE_Ak5yuE-p4S8RicdJgwhAU9BVcrn03cubSHcYShVTP8HL5DHyavfYkpw5p9WMNNLar4GP78-q1VdrYRthpn23n0Be58KlXNcPLrqV2VKcW6nra1wGySc6EpnoJHo5qze3azn4FvH95_XX5aXH75eLF8e7kwPUF00TGi7eA66wwSGo9IuaEzXGvGrbKD0cxg7thARm5pz0WPxIiY6JQmVLix787Am4N3W_XGWeNCSWqW2-Q3Ku1lVF7-_xL8JNdxJ5lACDHWBC9vBCn-qC4XuWlDcvOsgos1S0IoYnigDDX01QE1Keac3Hj8BiN5HY68Dkf-C6fBL-42dkRv02gAPgA__ez296jk8t1qdZD-BXXqoJ4</recordid><startdate>201910</startdate><enddate>201910</enddate><creator>Mishra, Rama K.</creator><creator>Clutter, Matthew R.</creator><creator>Blyth, Gavin T.</creator><creator>Kosciuczuk, Ewa M.</creator><creator>Blackburn, Amy Z.</creator><creator>Beauchamp, Elspeth M.</creator><creator>Schiltz, Gary E.</creator><creator>Platanias, Leonidas C.</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4180-5051</orcidid></search><sort><creationdate>201910</creationdate><title>Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening</title><author>Mishra, Rama K. ; Clutter, Matthew R. ; Blyth, Gavin T. ; Kosciuczuk, Ewa M. ; Blackburn, Amy Z. ; Beauchamp, Elspeth M. ; Schiltz, Gary E. ; Platanias, Leonidas C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4205-362bd9e3dec08b1f0ae93c7bb67dad9cb6c17e692f7d5478408f0683ab258ef43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>AML</topic><topic>Drug Discovery</topic><topic>eIF4E</topic><topic>Glide</topic><topic>Humans</topic><topic>IFD</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - enzymology</topic><topic>Mnk1</topic><topic>Mnk2</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>vHTS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mishra, Rama K.</creatorcontrib><creatorcontrib>Clutter, Matthew R.</creatorcontrib><creatorcontrib>Blyth, Gavin T.</creatorcontrib><creatorcontrib>Kosciuczuk, Ewa M.</creatorcontrib><creatorcontrib>Blackburn, Amy Z.</creatorcontrib><creatorcontrib>Beauchamp, Elspeth M.</creatorcontrib><creatorcontrib>Schiltz, Gary E.</creatorcontrib><creatorcontrib>Platanias, Leonidas C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemical biology & drug design</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mishra, Rama K.</au><au>Clutter, Matthew R.</au><au>Blyth, Gavin T.</au><au>Kosciuczuk, Ewa M.</au><au>Blackburn, Amy Z.</au><au>Beauchamp, Elspeth M.</au><au>Schiltz, Gary E.</au><au>Platanias, Leonidas C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening</atitle><jtitle>Chemical biology & drug design</jtitle><addtitle>Chem Biol Drug Des</addtitle><date>2019-10</date><risdate>2019</risdate><volume>94</volume><issue>4</issue><spage>1813</spage><epage>1823</epage><pages>1813-1823</pages><issn>1747-0277</issn><eissn>1747-0285</eissn><abstract>Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.</abstract><cop>England</cop><pmid>31260185</pmid><doi>10.1111/cbdd.13585</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4180-5051</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1747-0277 |
| ispartof | Chemical biology & drug design, 2019-10, Vol.94 (4), p.1813-1823 |
| issn | 1747-0277 1747-0285 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6800066 |
| source | MEDLINE; Access via Wiley Online Library |
| subjects | AML Drug Discovery eIF4E Glide Humans IFD Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - enzymology Mnk1 Mnk2 Molecular Docking Simulation Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - metabolism Protein Kinase Inhibitors - chemistry Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism vHTS |
| title | Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-07T22%3A08%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20novel%20Mnk%20inhibitors%20using%20mutation%E2%80%90based%20induced%E2%80%90fit%20virtual%20high%E2%80%90throughput%20screening&rft.jtitle=Chemical%20biology%20&%20drug%20design&rft.au=Mishra,%20Rama%20K.&rft.date=2019-10&rft.volume=94&rft.issue=4&rft.spage=1813&rft.epage=1823&rft.pages=1813-1823&rft.issn=1747-0277&rft.eissn=1747-0285&rft_id=info:doi/10.1111/cbdd.13585&rft_dat=%3Cproquest_pubme%3E2250619560%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2250619560&rft_id=info:pmid/31260185&rfr_iscdi=true |